23 research outputs found
Pharmacological activation of mGlu5 receptors with the positive allosteric modulator, VU0360172 modulates thalamic GABAergic transmission
Previous studies have shown that injection of the mGlu5 receptor positive allosteric modulator (PAM) VU0360172 into either the thalamus or somatosensory cortex markedly reduces the frequency of spike-and-wave discharges (SWDs) in the WAG/Rij model of absence epilepsy. Here we have investigated the effects of VU0360172 on GABA transport in the thalamus and somatosensory cortex, as possible modes of action underlying the suppression of SWDs. Systemic VU0360172 injections increase GABA uptake in thalamic synaptosomes from epileptic WAG/Rij rats. Consistent with this observation, VU0360172 could also enhance thalamic GAT-1 protein expression, depending on the dosing regimen. This increase in GAT-1 expression was also observed in the thalamus from non-epileptic rats (presymptomatic WAG/Rij and Wistar) and appeared to occur selectively in neurons. The tonic GABAA receptor current present in ventrobasal thalamocortical neurons was significantly reduced by VU0360172 consistent with changes in GAT-1 and GABA uptake. The in vivo effects of VU0360172 (reduction in tonic GABA current and increase in GAT-1 expression) could be reproduced in vitro by treating thalamic slices with VU0360172 for at least 1 hour and appeared to be dependent on the activation of PLC. Thus, the effects of VU0360172 do not require an intact thalamocortical circuit. In the somatosensory cortex, VU0360172 reduced GABA uptake but did not cause significant changes in GAT-1 protein levels. These findings reveal a novel mechanism of regulation mediated by mGlu5 receptors, which could underlie the powerful anti-absence effect of mGlu5 receptor enhancers in animal models
Schizophrenia: synthetic strategies and recent advances in drug design
YesSchizophrenia is a complex and unpredictable mental disorder which affects several domains of cognition and behaviour. It is a heterogeneous illness characterised by positive, negative, and cognitive symptoms, often accompanied by signs of depression. In this tutorial review, we discuss recent progress in understanding the target sites and mechanisms of action of second-generation antipsychotic drugs. Progress in identifying and defining target sites has been accelerated recently by advances in neuroscience, and newly developed agents that regulate signalling by the main excitatory neurotransmitters in the brain are surveyed. Examples of novel molecules for the treatment of schizophrenia in preclinical and clinical development and their industrial sponsors are highlighted.The Royal Society, The Academy of Medical Sciences, The Wellcome Trust, The Government Department of Business, Energy and Industrial Strategy and the British Heart Foundation, The University of Bradford
Targeting metabotropic glutamate receptors for novel treatments of schizophrenia
Abstract Support for the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia has led to increasing focus on restoring proper glutamatergic signaling as an approach for treatment of this devastating disease. The ability of metabotropic glutamate (mGlu) receptors to modulate glutamatergic neurotransmission has thus attracted considerable attention for the development of novel antipsychotics. Consisting of eight subtypes classified into three groups based on sequence homology, signal transduction, and pharmacology, the mGlu receptors provide a wide range of targets to modulate NMDAR function as well as glutamate release. Recently, allosteric modulators of mGlu receptors have been developed that allow unprecedented selectivity among subtypes, not just groups, facilitating the investigation of the effects of subtype-specific modulation. In preclinical animal models, positive allosteric modulators (PAMs) of the group I mGlu receptor mGlu5 have efficacy across all three symptom domains of schizophrenia (positive, negative, and cognitive). The discovery and development of mGlu5 PAMs that display unique signal bias suggests that efficacy can be retained while avoiding the neurotoxic effects of earlier compounds. Interestingly, mGlu1 negative allosteric modulators (NAMs) appear efficacious in positive symptom models of the disease but are still in early preclinical development. While selective group II mGlu receptor (mGlu2/3) agonists have reached clinical trials but were unsuccessful, specific mGlu2 or mGlu3 receptor targeting still hold great promise. Genetic studies implicated mGlu2 in the antipsychotic effects of group II agonists and mGlu2 PAMs have since entered into clinical trials. Additionally, mGlu3 appears to play an important role in cognition, may confer neuroprotective effects, and thus is a promising target to alleviate cognitive deficits in schizophrenia. Although group III mGlu receptors (mGlu4/6/7/8) have attracted less attention, mGlu4 agonists and PAMs appear to have efficacy across all three symptoms domains in preclinical models. The recent discovery of heterodimers comprising mGlu2 and mGlu4 may explain the efficacy of mGlu4 selective compounds but this remains to be determined. Taken together, compounds targeting mGlu receptors, specifically subtype-selective allosteric modulators, provide a compelling alternative approach to fill the unmet clinical needs for patients with schizophrenia
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Induction and Expression of Fear Sensitization Caused by Acute Traumatic Stress
Fear promotes adaptive responses to threats. However, when the level of fear is not proportional to the level of threat, maladaptive fear-related behaviors characteristic of anxiety disorders result. Post-traumatic stress disorder develops in response to a traumatic event, and patients often show sensitized reactions to mild stressors associated with the trauma. Stress-enhanced fear learning (SEFL) is a rodent model of this sensitized responding, in which exposure to a 15-shock stressor nonassociatively enhances subsequent fear conditioning training with only a single trial. We examined the role of corticosterone (CORT) in SEFL. Administration of the CORT synthesis blocker metyrapone prior to the stressor, but not at time points after, attenuated SEFL. Moreover, CORT co-administered with metyrapone rescued SEFL. However, CORT alone without the stressor was not sufficient to produce SEFL. In these same animals, we then looked for correlates of SEFL in terms of changes in excitatory receptor expression. Western blot analysis of the basolateral amygdala (BLA) revealed an increase in the GluA1 AMPA receptor subunit that correlated with SEFL. Thus, CORT is permissive to trauma-induced changes in BLA function
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Induction and Expression of Fear Sensitization Caused by Acute Traumatic Stress.
Fear promotes adaptive responses to threats. However, when the level of fear is not proportional to the level of threat, maladaptive fear-related behaviors characteristic of anxiety disorders result. Post-traumatic stress disorder develops in response to a traumatic event, and patients often show sensitized reactions to mild stressors associated with the trauma. Stress-enhanced fear learning (SEFL) is a rodent model of this sensitized responding, in which exposure to a 15-shock stressor nonassociatively enhances subsequent fear conditioning training with only a single trial. We examined the role of corticosterone (CORT) in SEFL. Administration of the CORT synthesis blocker metyrapone prior to the stressor, but not at time points after, attenuated SEFL. Moreover, CORT co-administered with metyrapone rescued SEFL. However, CORT alone without the stressor was not sufficient to produce SEFL. In these same animals, we then looked for correlates of SEFL in terms of changes in excitatory receptor expression. Western blot analysis of the basolateral amygdala (BLA) revealed an increase in the GluA1 AMPA receptor subunit that correlated with SEFL. Thus, CORT is permissive to trauma-induced changes in BLA function
PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems
Positive
allosteric modulators (PAMs) of the M<sub>1</sub> subtype
of muscarinic acetylcholine receptor have attracted intense interest
as an exciting new approach for improving the cognitive deficits in
schizophrenia and Alzheimer’s disease. Recent evidence suggests
that the presence of intrinsic agonist activity of some M<sub>1</sub> PAMs may reduce efficacy and contribute to adverse effect liability.
However, the M<sub>1</sub> PAM PF-06827443 was reported to have only
weak agonist activity at human M<sub>1</sub> receptors but produced
M<sub>1</sub>-dependent adverse effects. We now report that PF-06827443
is an allosteric agonist in cell lines expressing rat, dog, and human
M<sub>1</sub> and use of inducible cell lines shows that agonist activity
of PF-06827443 is dependent on receptor reserve. Furthermore, PF-06827443
is an agonist in native tissue preparations and induces behavioral
convulsions in mice similar to other ago-PAMs. These findings suggest
that PF-06827443 is a robust ago-PAM, independent of species, in cell
lines and native systems